[unreadable] [unreadable] Results from the Women's Health Initiative (WHI) clinical trial and observational epidemiologic studies strongly show that combined estrogen and progestin therapy (EPT) is associated with breast cancer risk. After the publication of the WHI study, there has been a shift in the type of EPT used in the United States. Some of these new alternatives are based on estradiol (E2) and testosterone derivatives as the progestin component. These preparations have been used in Europe for a while, and there is no evidence that these preparations will be better for the breast tissue than the classical EPT regimens used in the US. However, a number of uncertainties remain, and the role of these compounds on the breast is not completely understood. In the Postmenopausal Estrogen and Progestin Interventions (PEPI) trial, we described changes in mammographic density, a marker for breast cancer risk, in women randomized to EPT. We propose to use the same method and same reader for assessing mammographic density in women who have used E2 based EPT regimens. Factors that modify the effects of EPT on the breast may also be important. In the PEPI study we found large variations in mammographic density changes among women randomized to the same EPT. Further, changes in serum estrone levels predicted mammographic density changes in women randomized to EPT. It is possible that variations in hormone absorption or metabolism may predict who will develop such mammographic density increase. The proposed project takes advantage of data that have already been collected on women in the Norwegian Breast Cancer Screening Program. Both a high- and a low-dose E2 based EPT medications have been relatively commonly used in Norway until recently. We are proposing to assess mammographic density on 1648 women who have provided questionnaire data, buccal cells and whose mammograms from 1996- 2004 are in the process of being scanned in Oslo, Norway. The specific aims of this project are to determine the 1) mammographic density in women currently taking E2 based EPT as compared to that of non hormone users; 2) the mammographic density change in women who stopped taking E2 based EPT from one screening exam to the next; 3) the role of selected variants in genes encoding for hormone metabolism and action in predicting mammographic density in EPT users. [unreadable] [unreadable] [unreadable]